The long range goal of this project is to anatomically dissect the intrinsic circuit organization of the prefrontal cortex at light and electron microscopic levels in normal humans, monkeys, and in selected instances, schizophrenic brains. Emphasis continues to be placed on the cytoarchitecture, local circuits, and monoaminergic innervation of associational and selected sensory cortical regions, with reference to findings obtained on schizophrenic brains in this and other laboratories. The project is subdivided along three lines of inquiry. 1) In ongoing investigations of neuropathological changes in schizophrenic cortex, we propose to add a new cohort of cases as well as expand cytometric investigation to include area 8, the human frontal eyefields, and area 45, Broca's area; we hope to confirm and extend evidence of increased cell density and decreased neuropil obtained in Brodmann's area 9 and 46, and determine whether cellular changes are specific to association areas and, within these areas, to specific neuronal populations; 2) Studies of intrinsic circuitry in human prefrontal cortex will address whether increased cell density in schizophrenics is due to loss or rearrangement of intracortical connections and/or atrophy of dendritic arborizations using fluorescent tracers, e.g., diI, and Golgi impregnations, respectively. Inputs to identified inhibitory interneurons will also be examined in rhesus monkeys and human cortex in immunocytochemical analyses at the light and electron microscopic level; 3) We will proceed with the ultrastructural characterization of the synaptic architecture of chemically defined afferents on identified cortical targets, guided by the hypothesis that norepinephrine, serotonin, and acetylcholine each have preferential patterns of termination within the cortical mantle just as we demonstrated for the dopaminergic innervation. Double labeling immunocytochemical paradigms will also be used to reveal anatomical substrates of the interaction among these systems in the prefrontal cortex of rhesus monkeys, and ultimately in the human brain. The availability of neurotransmitter - and receptor-specific antibodies and mRNA probes which recognize receptor-synthesizing neurons, some of which are being developed in Project III of this proposed Center, will allow us to gain a comprehensive view of pre-and postsynaptic elements of specific neurotransmitter systems and thereby to gain a more explicit understanding of their psychoactive efforts.